Optimization of EphA2 antagonists based on a lithocholic acid core led to the identification of UniPR505, a new 3α-carbamoyloxy derivative with antiangiogenetic properties.
Angiogenesis Inhibitors
/ chemistry
Animals
Cell Proliferation
Chick Embryo
Chickens
Chorioallantoic Membrane
Humans
Lithocholic Acid
/ chemistry
Male
Models, Molecular
Neovascularization, Physiologic
/ drug effects
Phosphorylation
Polycyclic Compounds
/ chemistry
Prostatic Neoplasms
/ drug therapy
Protein Kinase Inhibitors
/ chemistry
Receptor, EphA2
/ antagonists & inhibitors
Structure-Activity Relationship
Tumor Cells, Cultured
Angiogenesis
EphA2
Lithocholic acid
Molecular modelling
Protein-protein interaction
SAR
Journal
European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510
Informations de publication
Date de publication:
01 Mar 2020
01 Mar 2020
Historique:
received:
29
07
2019
revised:
16
01
2020
accepted:
19
01
2020
pubmed:
31
1
2020
medline:
31
10
2020
entrez:
31
1
2020
Statut:
ppublish
Résumé
The EphA2 receptor has been validated in animal models as new target for treating tumors depending on angiogenesis and vasculogenic mimicry. In the present work, we extended our current knowledge on structure-activity relationship (SAR) data of two related classes of antagonists of the EphA2 receptor, namely 5β-cholan-24-oic acids and 5β-cholan-24-oyl l-β-homotryptophan conjugates, with the aim to develop new antiangiogenic compounds able to efficiently prevent the formation of blood vessels. As a result of our exploration, we identified UniPR505, N-[3α-(Ethylcarbamoyl)oxy-5β-cholan-24-oyl]-l-β-homo-tryptophan (compound 14), as a submicromolar antagonist of the EphA2 receptor capable to block EphA2 phosphorylation and to inhibit neovascularization in a chorioallantoic membrane (CAM) assay.
Identifiants
pubmed: 32000051
pii: S0223-5234(20)30050-7
doi: 10.1016/j.ejmech.2020.112083
pii:
doi:
Substances chimiques
Angiogenesis Inhibitors
0
Polycyclic Compounds
0
Protein Kinase Inhibitors
0
Lithocholic Acid
5QU0I8393U
Receptor, EphA2
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
112083Informations de copyright
Copyright © 2020 Elsevier Masson SAS. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.